Phagocytosis of infectious agents by Fc receptors for IgG (Fc gammaR) is a vital biological process for the innate immune system. However, the requisite molecular mechanisms involved in phagocytosis are poorly understood. Experiments from our laboratory and others indicate that Fc gammaR clustering is accompanied by activation of protein tyrosine kinases, resulting in tyrosine phosphorylation of a conserved motif of amino acids found in the cytoplasmic tail of immunoreceptors and termed the ITAM. Phosphorylation of ITAM tyrosines initiates recruitment of a variety of enzymes and adapter proteins through Src-homology 2 (SH2) and other protein interaction domains, which ultimately evoke biological responses. Signaling events beyond these early ones are unresolved and occasionally conflicting, especially regarding studies of Fc gammaRs unique to humans, where genetic analysis of signaling is difficult. Preliminary and published data from our laboratory indicate a role for Ptdlns 3-kinase and Syk in phagocytosis by human-restricted Fc gammaRIIa. We propose experiments to dissect the relationship between these important signaling enzymes, and those distal to them. A new experimental model is described that permits genetic analysis of the relationship between signaling molecules utilized by the human-specific IgG receptors. Second, experiments are proposed to understand the signaling mechanism employed by the tailless human-restricted IgG receptor, Fc gammaRIIIb. Last, we show new evidence and propose additional experiments to understand the role of the inositol phosphatase SHIP in regulating phagocytosis by Fc gammaRIIa. The results will provide a better understanding of molecular process involved in clearance of infectious agents in humans.